Abstract / Summary Peanut allergy is common, affecting 1-2% of children, and as opposed to most other childhood food allergies, usually persists lifelong. Even more concerning, for reasons that are not yet clear the prevalence of peanut allergy has increased 2-3 fold in the last 20 years. While the LEAP study convincingly demonstrated that peanut allergy could be prevented in about 80% of high risk infants by early peanut introduction, it is important to recognize that early peanut introduction is not universally successful in the prevention of peanut allergy. For example, 2% of the enrolled babies were already allergic, defined by a failed oral peanut challenge at study entry, and an additional 11% were assumed to be allergic based on a large peanut prick skin test and therefore excluded from the baseline challenge. This phenotype of babies with exceptionally early onset peanut allergy not only presents an unmet need from a clinical standpoint, since most will go on to have lifelong peanut allergy, they also provide a unique opportunity to study the underlying mechanisms for the development of food allergy. In this project, we will have the opportunity to characterize these infants from both a clinical and mechanistic standpoint, comparing them to their peers who have either no peanut sensitization or sensitization without allergy. Then, as our primary aim, we will study the safety and efficacy of peanut oral immunotherapy in this cohort, which to our knowledge will be the earliest initiation of any form of specific immunotherapy for the treatment of food allergy. We will accomplish this through the following specific aims: 1) To conduct a double- blind, placebo-controlled (DBPC) study of peanut OIT in 4 to 11 month old infants with peanut allergy. We hypothesize that treatment at this early age will be safe and effective, inducing not just a high rate of desensitization but also of sustained unresponsiveness (SU), far higher than has been demonstrated in older children and adolescents. 2) To characterize a cohort of infants with early onset peanut allergy, or deemed to be at high risk for the development of peanut allergy, who will be categorized for this study into three distinct subsets: those who are not peanut sensitized or allergic, those who are sensitized but not allergic, and those who have already developed clinical peanut allergy at the time of recruitment. 3) To collaborate with the investigators of the Biomarker Facility and Opportunity Fund to carefully select samples for more detailed mechanistic studies, potentially including metabolomics, microbiomics, epigenomics, and CyTOF, in addition to the usual biomarkers to be used in the immunologic profiling in Aim 1. We believe that the OIT trial will have a profound impact on the future treatment of peanut and other food allergies, and that this study will be highly informative in defining the clinical and immunologic factors that are most important in the development of peanut allergy.